Airway epithelium as an effector of inflammation: molecular regulation of secondary mediators

Abstract

Deleterious environmental stimuli cause the airway epithelium to respond with increased secretions of mucus, reaction of oxygen/nitrogen species, changes in ciliary beating, and the influx of inflammatory cells. The epithelium is a target for factors released by infiltrating inflammatory cells, and has recently been shown to serve as an effector of such inflammation. Molecular mechanisms regulating production of secondary inflammatory mediators (cytokines, lipid mediators, and reactive oxygen/nitrogen species) have yet to be fully described.This report reviews the production of secondary mediators by epithelial cells and by airway epithelium. Lipid mediators are enzymatically produced by the airway epithelium in response to primary mediators. Molecular mechanisms regulating the production of cyclo-oxygenase, lipoxygenase and prostaglandin synthase are discussed, along with the potential of lipid mediators to produce inflammation. The molecular regulation of nitric oxide production is also described in the context of its role as a signalling molecule in pathways regulating secretion of mucus, ciliary motion, and intercellular adhesion molecule-1 (ICAM-1) expression. The production of cytokines by the airway epithelium is shown to play a role in causing inflammation associated with respiratory diseases. Particular attention is paid to molecular mechanisms governing the expression of tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-8 (IL-8).

Cytoplasmic deposition of NFκB decoy oligonucleotides is insufficient to inhibit bleomycin-induced pulmonary inflammation

“…IL-6 has been shown to be involved in bleomycin-induced inflammation 28,29 and is produced by a variety of cell types, including epithelial cells and macrophages. 30,31 There is also good evidence that secretion of IL-6 is regulated through NF B 32 and NF B consensus binding sites have been identified in the promoter of the IL6 gene. 33,34 We also measured the effect of NF B decoy ODN on total and differential cell counts, as it is well documented that inflammatory cell chemokines, such as macrophage inflammatory protein-1␣ and macrophage inflammatory protein-2, which are involved in the generation of bleomycin-induced lung damage, 28,35 are regulated through NF B.…”

Regulation of epithelium-specific Ets-like factors ESE-1 and ESE-3 in airway epithelial cells: potential roles in airway inflammation

“…A number of studies have suggested that airway epithelia play an active role in the development of chronic airway inflammatory diseases [1-3, 7, 39]. For example, the airway epithelia secrete a variety of cytokines to initiate immune responses [1,3], and contribute to the irreversible structural changes of the airway that are referred to as 'airway remodeling', which occurs in patients with asthma [3,7]. Our findings that both ESE-1 and ESE-3 are highly inducible in bronchial epithelial cells suggest that these transcription factors may be critical in the regulation of airway inflammation.…”

“…IL-6 is a pleiotropic cytokine with a variety of biological activities not only in immune regulation, hematopoiesis and oncogenesis, but also in inflammation [44]. Moreover, IL-6 is considered a key modulator in chronic airway inflammatory disease such as asthma [1,45,46]. Airway epithelial cells can synthesize and release IL-6 in response to inflammatory stimuli.…”

“…In addition to acting as a physical barrier, airway epithelial cells are involved in the manifestation of airway inflammatory diseases [1][2][3]. In response to environmental perturbations, airway epithelia can produce and release a variety of inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), IL-6 and IL-8.…”

“…For example, TNF-α has been shown to alter epithelial cell permeability, as well as to stimulate IL-6, IL-8 and GM-CSF expression [3]. A number of studies have shown that the epithelium of patients who have airway inflammatory diseases is structurally and functionally altered [4][5][6][7], and that bronchial epithelial cells that are isolated from patients with asthma or cystic fibrosis (CF) express increased levels of cytokines [1,3]. Therefore, it is important to fully understand gene regulation in airway epithelium in order to alleviate airway inflammatory diseases.…”